1. Field of the Invention
The present invention relates to substituted 3-(biphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-ones of the formula (Ia) for therapeutic purposes, to pharmaceutical compositions comprising the compounds according to the invention and to their use in therapy, in particular for the prophylaxis and/or therapy of tumor disorders.
2. Description of Related Art
Acetyl-CoA carboxylases (ACCs) play a key role in cellular fatty acid homeostasis. ACCs are biotin-containing enzymes which catalyze the carboxylation of acetyl-CoA to malonyl-CoA in an ATP-dependent manner (Kim, 1997; Harwood, 2005; Tong, 2005). This reaction, which proceeds as two half-reactions, a biotin carboxylase (BC) reaction and a carboxyltransferase (CT) reaction, is the first introductory step of fatty acid biosynthesis and is the rate-determining step of the pathway. Two human ACC isoforms, ACC1 and ACC2, which are encoded by two different genes, are known (LuTFI ABU-ELHEIGA et al, 1995, Jane WIDMER, et al. 1996). ACC1 is expressed in lipogenic tissue (liver, fatty tissue), localized in the cytosole and fills the malonyl-CoA pool which serves as C2 unit donor for the de novo synthesis of long-chain fatty acids by FASN and subsequent chain extension. ACC2 is expressed mainly in oxidative tissues (liver, heart, skeletal muscle) (Bianchi et al., 1990; Kim, 1997), is associated with mitochondria and regulates a second malonyl-CoA pool. This regulates fatty acid oxidation by inhibiting carnitine palmityltransferase I, the enzyme which facilitates entry of long-chain fatty acids into the mitochondria for β oxidation (Milgraum L Z, et al., 1997, Widmer J. et al., 1996). Both enzymes show very high sequence homology and are regulated in a similar manner by a combination of transcriptional, translational and posttranslational mechanisms. Both in humans and in animals, ACC activity is highly controlled by a number of dietary, hormonal and other physiological mechanisms such as forward allosteric activation by citrate, feedback inhibition by long-chain fatty acids, reversible phosphorylation and/or inactivation or modulation of enzyme production by modified gene expression.
ACC1 knockout mice are embryonally lethal (Swinnen, et al., 2006, Abu-Elheiga, et al. 2005). ACC2 knockout mice show reduced malonyl-CoA concentrations in skeletal and heart muscle, increased fatty acid oxidation in the muscle, reduced liver fat levels, reduced amounts of total body fat, increased levels of UCP3 in the skeletal muscle (as an indication of higher energy expenditure), a reduced body weight, reduced plasma concentrations of free fatty acids, reduced plasma glucose levels, reduced amounts of tissue glycogen, and they are protected against diet-induced diabetes and obesity (Abu-Elheiga et al., 2001, 2003; Oh et al., 2005).
In addition to the involvement in fatty acid synthesis in lipogenic tissues and fatty acid oxidation in oxidative tissues, in many tumor cells an upregulation of ACC and an increased lipogenesis was observed (Swinnen, et al., 2004, Heemers, et al., 2000, Swinnen, et al., 2002, Rossi, et al., 2003, Milgraum, et al., 1997, Yahagi, et al., 2005). With very high probability, this phenotype contributes to the development and progression of tumors; however, the regulatory mechanisms involved still have to be clarified.
EP0454782 and U.S. Pat. No. 5,759,837 protect the use of fatty acid synthesis inhibitors for inhibiting tumor cell growth. Cyclic ketoenols have not been disclosed.
A number of substances capable of inhibiting plant and/or insect ACC have been discovered.
The PCT patent application PCT/EP99/01787, published as WO 99/48869, which corresponds to the European Patent EP 1 066 258 B1, refers to novel arylphenyl-substituted cyclic ketoenols, to a plurality of processes for their preparation and to their use as pesticides and herbicides.
3-Acylpyrrolidine-2,4-diones have already been described as having pharmaceutical properties (S. Suzuki et al. Chem. Pharm. Bull. 15 1120 (1967)). Furthermore, N-phenylpyrrolidine-2,4-diones have been synthesized by R. Schmierer and H. Mildenberger (Liebigs Ann. Chem. 1985, 1095). A biological activity of these compounds has not been described.
EP-A-0 262 399 and GB-A-2 266 888 disclose compounds of a similar structure (3-arylpyrrolidine-2,4-diones) of which, however, no herbicidal, insecticidal or acaricidal activity has become known. Unsubstituted bicyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-355 599, EP-A-415 211 and JP-A-12-053 670) and substituted monocyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-377 893 and EP-A-442 077) are known to have herbicidal, insecticidal or acaridical activity.
Additionally known are polycyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-442 073) and 1H-arylpyrrolidinedione derivatives (EP-A-456 063, EP-A-521 334, EP-A-596 298, EP-A-613 884, EP-A-613 885, WO 95/01 971, WO 95/26 954, WO 95/20 572, EP-A-0 668 267, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36 868, WO 97/43275, WO 98/05638, WO 98/06721, WO 98/25928, WO 99/24437, WO 99/43649, WO 99/48869, WO 99/55673, WO 01/17972, WO 01/23354, WO 01/74770, WO 03/013249, WO 03/062244, WO 2004/007448, WO 2004/024 688, WO 04/065366, WO 04/080962, WO 04/111042, WO 05/044791, WO 05/044796, WO 05/048710, WO 05/049569, WO 05/066125, WO 05/092897, WO 06/000355, WO 06/029799, WO 06/056281, WO 06/056282, WO 06/089633, WO 07/048,545, DEA 102 00505 9892, WO 07/073,856, WO 07/096,058, WO 07/121,868, WO 07/140,881, WO 08/067,873, WO 08/067,910, WO 08/067,911, WO 08/138,551, WO 09/015,801, WO 09/039,975, WO 09/049,851, WO 09/115,262, WO10/052,161, WO 10/063,378, WO 10/063,670, WO10/063,380, WO10/066,780, WO10/102,758, WO2010/135914, WO2011/067131, WO2011/067135, WO2011/067203 and WO2011/067240.
Furthermore known are ketal-substituted 1H-arylpyrrolidine-2,4-diones from WO 99/16748 and (spiro)-ketal-substituted N-alkoxyalkoxy-substituted arylpyrrolidinediones from JP-A-14 205 984 and Ito M. et. al., Bioscience, Biotechnology and Biochemistry 67, 1230-1238, (2003). Moreover, WO 06/024411 discloses herbicidal compositions comprising ketoenols.
WO 2008/022725 discloses 4′-biphenyl-substituted tetronic acid derivatives for the therapy of viral disorders.
WO 2005/089118 and WO2007/039286 disclose, in a general manner, nitrogen-containing bicyclic structures for therapy; however, 5″-biphenyl-substituted cyclic ketoenols are not specifically mentioned.
Surprisingly, it has now been found that a specific subgroup of the aryl-substituted cyclic ketoenols described in the prior art also inhibit human ACC and are suitable for the therapy of disorders.
Here, it was unforseeable whether and which of the structures known as insecticides or herbicides achieve the object of the invention, that is represent structures which can be used in the therapy of human disorders.
The applicant is not aware that 3-(biphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-ones of the formula (Ia) according to the present invention have been described in the prior art for the therapy of disorders, in particular not for the therapy of tumor disorders.